Reference Detail

Ref Type

Journal Article

PMID

(30266815)

Authors

Sayles LC, Breese MR, Koehne AL, Leung SG, Lee AG, Liu HY, Spillinger A, Shah AT, Tanasa B, Straessler K, Hazard FK, Spunt SL, Marina N, Kim GE, Cho SJ, Avedian RS, Mohler DG, Kim MO, DuBois SG, Hawkins DS, Sweet-Cordero EA

Title

Genome-Informed Targeted Therapy for Osteosarcoma.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Cancer discovery	9	1	2019 01	46-63	Cancer Discov

URL

Abstract Text

Osteosarcoma is a highly aggressive cancer for which treatment has remained essentially unchanged for more than 30 years. Osteosarcoma is characterized by widespread and recurrent somatic copy-number alterations (SCNA) and structural rearrangements. In contrast, few recurrent point mutations in protein-coding genes have been identified, suggesting that genes within SCNAs are key oncogenic drivers in this disease. SCNAs and structural rearrangements are highly heterogeneous across osteosarcoma cases, suggesting the need for a genome-informed approach to targeted therapy. To identify patient-specific candidate drivers, we used a simple heuristic based on degree and rank order of copy-number amplification (identified by whole-genome sequencing) and changes in gene expression as identified by RNA sequencing. Using patient-derived tumor xenografts, we demonstrate that targeting of patient-specific SCNAs leads to significant decrease in tumor burden, providing a road map for genome-informed treatment of osteosarcoma. SIGNIFICANCE: Osteosarcoma is treated with a chemotherapy regimen established 30 years ago. Although osteosarcoma is genomically complex, we hypothesized that tumor-specific dependencies could be identified within SCNAs. Using patient-derived tumor xenografts, we found a high degree of response for "genome-matched" therapies, demonstrating the utility of a targeted genome-informed approach.This article is highlighted in the In This Issue feature, p. 1.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
PTEN loss	osteosarcoma	sensitive	MK2206	Preclinical - Pdx	Actionable	In a preclinical study, a patient derived xenograft (PDX) model of osteosarcoma with biallelic loss of PTEN was sensitive to treatment with MK2206, demonstrating reduced tumor growth and increased apoptotic activity (PMID: 30266815).	30266815
PTEN loss	osteosarcoma	sensitive	Sirolimus	Preclinical - Pdx	Actionable	In a preclinical study, a patient derived xenograft (PDX) model of osteosarcoma with biallelic PTEN loss was sensitive to treatment with Rapamune (sirolimus), demonstrating reduced tumor growth and increased apoptotic activity (PMID: 30266815).	30266815